Preparation of ketocholanic acids



Patented Sept. 12, 1950 PREPARATION or KETOCHOLANIC ACIDS Robert H.Siiierd, Clarendon Hills, 111., assi'gnor to Armour and Company,Chicago, 111., a corporation of Illinois No Drawing. Continuation ofapplication Serial No. 548,795, August 9, 1944. This application March5, 1948, Serial No. 13,321 I '7 Claims.

This invention relates to the preparation of ketocholanic acids fromcholanic acid derivatives, and more particularly to a process for thecontrolled oxidation of cholanic acid deriva tives having a hydroxygroup to produce ketocholanic acids therefrom. Such cholanic acidderivatives will be called hydroxycholanic acids in this specificationand claims.

This application constitutes a continuation of my copending applicationSerial No. 548,795 for Preparation of Ketocholanic Acids, filed August9, 1944, now abandoned.

Dehydrocholic acid has heretofore been prepared by the oxidation ofcholic acid, but the processes used have not been entirely satisfactoryin that the reaction was difficult to handle and control and yields havenot been great.

Anobject of the invention is to provide an efficient economical processfor oxidizing hydroxycholanic acids to produce ketocholanic acids.Another object is to provide an oxidation process by which a relativelyhigh yield of a ketocholanic acid may be obtained from a hydroxycholanicacid. Still another object is to provide a process for preparing aketocholanic acid from a hydroxycholanic acid in which the reaction maybe readily handled and controlled. Still a further object is to providean oxidation process for producing a ketocholanic acid in whichahydroxycholanic acid is slowly and gradually brought into contact withan oxidizing agent to produce a controlled oxidation reaction. Theprocess contemplates the reaction of a hydroxycholanic acid in anaqueous medium which contains a Water-miscible organic solvent in whichthe hydroxycholanic acid is soluble with a suitable oxidizing agent,such as chromic acid. Preferably, the organic solvent in which thehydroxycholanic acid is soluble is present in a quantity sufficient todissolve only a portion of the hydroxycholanic acid. Accordingly, as thereaction proceeds and hydroxycholanic acid is converted into theketocholanic acid, additional hydroxycholanic acid is dissolved and istherefore reacted in solution with the oxidizing agent. Thehydroxycholanic acid may be cholic acid or cholalic acid, thedesoxycholic acids, lithocholic acids, etc., and may be in any suitableform, such as cholic acid obtained from bile and animal excretions by aprocess such as that described in my co-pending application Serial No.517,435, filed January '7, 1944, now Pat. No. 2,438,- 232, dated March23, 1948, for Preparation of Cholic Acid.

The solutionor medium in which the reaction occurs is an aqueous mediumcontaining a water-miscible organic solvent in which the hydroxycholanicacid is soluble. Acetone has been found to be an excellent solvent forthis purpose since it is miscible with water, is not readily oxidizable,and is a fairly goodsolvent for-hydroxycholanic acid. Acetone also hasthe advantage that it is readily available commercially and. isrelatively inexpensive. Accordingly, it is usually not necessary torecover the acetone used in the process, although this may be done ifdesired.

Any other Water-miscible organic solvent having the desiredcharacteristics and properties may be used. For example, acetic acid ora water-soluble higher aliphatic carboxylic acid may be used. Similarly,higher ketones which are water-miscible, such as methyl ethyl ketone,for example, may be used.

Although any suitable oxidizing agent may be used, chromic acid has beenfound to be very satisfactory for this purpose. When chromic acid is tobe used, the original solution or suspension of the hydroxycholanic acidin the aqueous medium containing the water-miscible inorganic solventmay also contain an acidifying agent so that the reaction may be carriedout by mixing the medium containing the hydroxycholanic acid with achromate salt, such as sodium bichromate. For example, the acidifyingagent may consist of sulfuric acid or other suitable acid which does notenter into the reaction.

The hydroxycholanic acid may be suspended with agitation in an aqueousmedium containing between 10% and 25% of sulfuric acid and between 15%and 35% of acetone, the proportions being by weight. Preferably, thequantity of sulfuric acid used is in the neighborhood of 20% and thequantity of acetone used is in the neighborhood of 25%. A portion of thehydroxycholanic acid is dissolved in the mixture and the balance of thehydroxycholanic acid is maintained in a dispersion in the medium bymeans of the agitation.

- The'oxidation reaction is carried out by adding a suitable oxidizingagent, such as sodium bichromate, to the mixture while violentlyagitating the entire mixture. During the addition of the oxidizingagent, the mixture will tend to become heated and may be cooled to keepthe temperature relatively constant. Preferably, the reaction is carriedout at a temperaturelbetween 28 C. and 37 0. As the oxidizing agent isadded to the mixture, the hydroxycholanic acid reacts with the oxidizingagent to form the corresponding ketocholanic acid, and additionalhydroxycholanic acid becomes dissolved in the mixture and also reactswith the oxidizing agent. In this way, a gradually controlled oxidationof the hydroxycholanic acid is readily carried out.

As the reaction progresses, a ketocholanic acid is formed whichseparates from the solution, and when the reaction is complete theketocholanic acid is removed by filtration.

Specific examples of the process are as follows:

Example I 20 lbs. of purified cholic acid is suspended in a mixture of23 lbs. concentrated sulfuric acid, 50 lbs. of water and 35 lbs.acetone, at a temperature of 30 C. To this mixture is added a watersolution of 16 lbs. sodium bichromate, with vigorous agitation andcooling to effect a temperature control in the range of 30-35 C. Afterall the bichromate solution has been added, dehydrocholic acid isremoved by filtration. It may be purified in any of the usual ways.

Example II 100 lbs. of semi-refined cholic acid is suspended in amixture of 118 lbs. sulfuric acid, 30 gals. of acetone and 40 gals. ofwater. To the mixture is added 40 gals. of a water solution containing85 lbs. technical grade sodium bichromate, keeping the temperature ofthe mixture between 28 and 37 C. After the bichromate has been added,the dehydrocholic acid formed by the oxidation of the cholic acidisremoved by filtration and recrystallized from a suitable solvent.

Although the preferred method of carrying out the reaction is to slowlyintroduce a water solution of the oxidizing agent, such as sodiumbichromate, into the mixture containing the hydroxycholanic acid andvigorously agitating the mixture during the addition, if desired, thehydroxycholanic acid in the medium may be slowly added to the oxidizingagent. In any event, the mixing may be carried out slowly and graduallyand a controlled reaction obtained.

As already indicated, the chromic acid or other water-soluble oxidizingagent is added in a quantity greater than that required for reactionwith the hydroxy cholanic acid dissolved in the me: dium. The amount ofhydroxy cholanic acid which it is desired to react with the chromic acidis controlled by the quantity of the water-miscible organic solventintroduced. Thus, the amount of hydroxy cholanic acid going intosolution, and

thereby made available for reaction, is metered by the solvent employed.

The chromic acid or other water-soluble oxidizing agent may be added allat one time or through a period in the process. If the chromic acid isadded largely at one time, more cooling coils are required to maintainthe desired temperature range. It is more convenient usually to employless cooling and to feed the oxidizing agent at a slower rate over aperiod of the operation. For example, the usual operation requires aperiod of 45 minutes. The chromic acid is preferably introduced slowlyinto the mixture for from to 30 minutes. After the first 30 minutes ofoperation, I prefer to agitate the material for another minutes, whichcompletes the operation.

In maintaining the preferred temperatures of 28-37 C., the lower rangeof temperatures is easily maintained without employing special coolingmeans when the chromic acid is introduced at a slow rate. At a selectedtemperature, the amount of oxidizing agent present in the mixture isgreater than that required for reaction with the hydroxy cholanic acidin solution in the medium, and hence the medium effectively serves as ametering for the amount of hydroxy cholanic acid being acted upon by thechromic acid. The operator need observe only the temperature and avoidany excessive feeding of chromic acid which would bring about atemperature rise above the desired reaction temperatures. However, if hedesires to add additional chromic acid, this may be done by the additionof increased cooling means.

The process results in a high yield while being accomplished within avery brief interval of time. By the use of the metering step described,in which a selected amount of water-miscible organic solvent isemployed, a controlled reaction is effected without carefully observingthe amount of oxidizing agent added, thus permitting an extensivereaction between the materials to be carried out in a modicum of time.While the ordinary process requires only 45 minutes, the period may bestill further shortened through the use of more extensive cooling means,as above indicated.

If the water-miscible organic solvent were not employed, the addition ofthe chromic acid would result in rapid oxidation, producing a gummyproduct and a difficultly-dispersible tar. To avoid this difficulty, ithas heretofore been proposed by Eoedeclser (U. S. Patent No. 1,933,003)that xylene be employed as a dispersing agent and that all of the cholicacid be kept out of solution so that oxidation can occur only at thesurface interface. The diliculty with this process is the long period oftime required for the operation. Since oxidation occurs only at theinterface, periods of from 3 to 6 hours are required for the operation,and further it is necessary that the chromic acid be added drop by dropor in small quantities.

In the present process, the oxidation is accomplished in a very shorttime. Instead of keeping all of the cholic acid out of solution, I put apredetermined amount of cholic acid into solution and oxidize thisportion. Further, as the reaction continues, the equilibrium is shiftedand more hydroxy cholanic acid goes into solution. If a faster reactionis desired, a greater amount of water-miscible organic solvent is added,or if a slower reaction is desired, a lesser amount 0! the solvent isadded. By metering the amount of hydroxy cholanic acid going intosolution through the addition of selected amounts of the organicsolvent, the entire reaction can be controlled ellectively and completedin a period less than 45 minutes.

Although the invention has been described in connection with certainspecific examples, it will be apparent that modifications and changesmay be without departing from the spirit and scope of the invention.

I claim:

1. A process for preparing a ketocholanic acid, comprising dispersing ahydroxycholanic acid in an aqueous medium containing acetone to dissolveonly a portion of the hydroxycholanic acid, and mixing the medium havingthe hydroxycholanic acid dispersed therein with a proportion of awater-soluble oxidizing agent greater than that required for reactionwith the hydroxycholanic acid dissolved in said medium.

2. A process for preparing a ketocholanic acid,

comprising dispersing a, hydroxycholanic acid in an aqueous mediumcontaining acetone to dissolve only a portion of the hydroxycholanicacid, and slowly mixing a water solution of watersoluble chromate withthe medium having the hydroxycholanic acid dispersed therein and in aquantity greater than that required for reaction with said dissolvedhydroxycholanic acid.

3. A process for preparing a ketocholanic acid, comprising dispersing ahydroxycholanic acid in an aqueous medium containing a sufficientquantity of acetone to dissolve a portion only of the hydroxycholanicacid, and slowly mixing an aqueous solution of a water-soluble chromatewith the medium containing the hydroxycholanic acid dispersed thereinwhile agitating the mixture and maintaining the temperature thereofsubstantially constant, the chromate solution being added in quantitygreater than that required for reaction with the hydroxycholanic aciddissolved in said medium.

4. A process for preparing a ketocholanic acid, comprising dispersing ahydroxycholanic acid in an aqueous medium containing a suflioientquantity of acetone to dissolve a portion only of the hydroxycholanicacid, and slowly mixing an aqueous solution of a water-soluble chromatewith the medium containing the dispersed hydroxycholanic acid at atemperature in the neighborhood of 28 C. to 37 C. while agitating themixture, the mixture containing also an acidifying agent and saidoxidizing agent being added in a quantity greater than that required forreaction with the said dissolved hydroxycholanic acid at the time ofaddition of the hydroxycholanic acid.

5. A process for preparing a ketocholanic acid, comprising dispersing ahydroxycholanic acid in an aqueous medium containing an acidifying agentand a sufficient quantity of acetone to dissolve a portion only of thehydroxycholanic acid, and slowly adding to the medium containing thedispersed hydroxycholanic acid an aqueous solution of a water-solublechromate while maintaining the temperature of the mixture in theneighborhood of 28 C. to 37 0., and agitating the mixture.

6. A process for preparing a ketocholanic acid, comprising dispersing ahydroxycholanic acid in an aqueous medium containing in the neighborhoodof to sulfuric acid and in the neighborhood of 15% to acetone, thepro- 1. portions being by weight, and slowly mixing with the medium anaqueous solution of a water-soluble chromate while maintaining thetemperature of the mixture in the neighborhood of 28 C. to 37 C., andwhile agitating the mixture.

7. A process for preparing a ketocholanic acid, comprising dispersing ahydroxycholanic acid in an aqueous medium containing a sufficientquantity of acetone to dissolve a portion only of the hydroxycholanicacid, the acetone being in a proportion of about 15% to 35% by weight,and mixing an aqueous solution of a water-soluble oxidizing agent withthe medium containing the dispersed hydroxycholanic acid at atemperature of about 28 C. to 37 Cr ROBERT H. SIFFERD.

REFERENCES CITED UNITED STATES PATENTS Name Date Boedecker Oct. 31, 1933Number

1. A PROCESS FOR PREPARING A KETOCHOLANIC ACID, COMPRISING DISPERSING AHYDROXYCHOLANIC ACID IN AN AQUEOUS MEDIUM CONTAINING ACETONE TO DISSOLVEONLY A PORTION OF THE HYDROXYCHOLANIC ACID, AND MIXING THE MEDIUM HAVINGTHE HYDROXYCHOLANIC ACID DISPERSED THEREIN WITH A PROPORTION OF AWATER-SOLUBLE OXIDIZING AGENT GREATER THAN THAT REQUIRED FOR REACTIONWITH THE HYDROXYCHOLANIC ACID DISSOLVED IN SAID MEDIUM.